Effects on serotonergic neurotransmission underlie the clinical therapeutic effects of serotonin reuptake inhibitors (SSRIs), the class of drugs most frequently prescribed for the treatment of depression. Nevertheless, very little information is available about how SSRIs produce their behavioral effects. Research supported by this project examines the pharmacological and physiological basis underlying the antidepressant behavioral effects of SSRIs and other putative serotonergic antidepressants. The behavioral effects of antidepressant drugs are studied using the rat forced swimming test, a behavioral test that successfully predicts the clinical effects of antidepressant drugs. A version of the rat forced swimming test developed by this laboratory is used that measures the core response of immobility and component active behaviors and distinguishes antidepressants pharmacologically selective for serotonergic and catecholamine systems. The neurochemical effects of antidepressants and forced swimming are studied using in vivo microdialysis, which permits the release of 5-HT to be measured in discrete brain regions in awake unrestrained animals. The proposed research program will continue to investigate the neural substrates underlying the antidepressant behavioral effects of SSRIs. The first specific aim will characterize and distinguish the role of serotonin and catecholamine systems in the behavioral effects of an extended series of antidepressant drugs in the forced swimming test. Studies will also identify 5-HT receptor subtypes that are involved in the behavioral effects of SSRIs and that are likely to produce antidepressant effects. The second specific aim will employ the neurochemical depletion of 5-HT to establish the role of intact serotonergic neurons in the behavioral effects of different types of antidepressant drugs. Studies involving localized depletion of 5-HT will identify the brain regions likely to be associated with the production of their behavioral effects. The third specific aim will understand how the alterations of 5-HT release produced by acute stress in the forced swimming test, and modifications of 5-HT neurotransmission produced by antidepressant treatments, are related to the production of the behavioral effects of antidepressant drugs in this test. The results of the proposed work should have important implications for our understanding of the mechanisms involved in the behavioral effects of SSRIs in the clinical treatment of depression.